Numerous organic compounds bearing a trifluoromethyl group are valuable as pharmaceuticals and agrochemicals. Examples of such pharmaceuticals bearing trifluoromethyl groups include Fluoxetine (Prozac®), Celecoxib (Celebrex®), Mefloquine (Lariam®), Leflunomide (Arava®), Nilutamide (Nilandron®), Dutasteride (Avodart®), Bicalutamide (Casodex®), Aprepitant (Emend). Examples of such agrochemicals include Trifluralin, Fipronil, Fluazinam, Penthiopyrad, Picoxystrobin, Fluridone and Norflurazon. Furthermore, some useful monomers, composites, materials for electronics, including electro- and photoluminescent compounds, solvents and valuable chemical building blocks and intermediates have the trifluoromethyl moiety. There is a need for simple, economic and environmentally benign methods to introduce the trifluoromethyl group into organic molecules in order to prepare active ingredients of agrochemicals and pharmaceuticals, as well as other useful compounds and materials.
A number of synthetic methods to produce such compounds have been developed. Particularly useful in this respect are copper reagents bearing the trifluoromethyl group. These trifluoromethyl copper reagents have been reviewed by Burton et al. (“Fluorinated organometallic compounds”, Top. Curr. Chem. 1997, 193, 45 and Tetrahedron 1992, 48, 189), McClinton et al. (“Trifluoromethylations and related reactions in organic chemistry”, Tetrahedron 1992, 48, 6555), Kumadaki (“Trifluoromethylation of Organic Compounds and Related Reactions”, Synthesis 2010, 1865) and Schlosser (“CF3-Bearing Aromatic and Heterocyclic Building Blocks”, Angew. Chem. Int. Ed. 2006, 45, 5432). Various chemicals can be used to prepare such trifluoromethyl copper reagents, including CF3I, CF3Br, CF2Br2, CF2BrCl, CF2Cl2, (CF3)2Hg, CF3SiMe3, CF3CO2X (X═Na, K, CH3), FSO2CF2CO2CH3, as well as trifluoromethyl derivatives of Zn and Cd. Some of these compounds are toxic, some costly, some explosive and some environmentally malevolent, being ozone depleters.
Trifluoromethane (fluoroform or HFC-23), HCF3, is readily available and inexpensive, has low toxicity and is not an ozone depleter. However, fluoroform has rarely been used to make trifluoromethyl copper compounds. For example, HCF3 can be iodinated to CF3I (Nagasaki “Study on a novel catalytic reaction and its mechanism for CF3I synthesis.” Catalysis Today 2004, 88, 121), which then can be contacted with copper metal to produce a trifluoromethyl, copper compound (McLoughlin and Thrower “Route to fluoroalkyl-substituted aromatic compounds involving fluoroalkylcopper intermediates.” Tetrahedron 1969, 25, 5921). Alternatively, fluoroform can be deprotonated to produce the highly unstable CF3− anion that easily decomposes into fluoride and difluorocarbene, prompt to form side products. For this reason, such reactions require low temperatures (below −20° C.), as well as the presence of N,N-dimethylformamide to stabilize the trifluoromethyl anion in the form of hemiaminolate, and are still hard to control. These compounds also suffer from lower reactivity than other trifluoromethyl copper compounds. However, no one has ever disclosed a direct synthesis of a trifluoromethyl copper compound directly from a copper reagent and fluoroform. Folleas et al. (“Fluoroform: an efficient precursor for the trifluoromethylation of aldehydes”, Tetrahedron 2000, 56, 275) write: “Our first attempts to generate trifluoromethyl metal with M=Cu and Zn from fluoroform were based on the metallation concept with basic organocopper and organozinc derivatives in order to directly obtain the trifluoromethyl copper or zinc derivatives. However, whatever the organometallic used ((nBu)2CuLi, (nBu)2CuCNLi2, (nBu)3CuCNLi3, tert-Bu2CuCNLi2, Et2Zn, (nBu)3ZnLi, AllylZnBr, . . . ) in different conditions (heating, sonication, in pressurised flask) or different solvents (Et2O, THF, HMPA) no trace of the corresponding trifluoromethyl organometallic was detected”. Other basic Cu(I) compounds are known, for example dialkoxy copper(I) sodium derivatives (NaCu(OC(CH3)3)2), polymers or oligomers thereof, and Na4Cu4(OC(C2H5)3)8. Some dialkoxy copper (I) lithium derivatives are also, known: Li4Cu4(OC(CH3)3)8 and LiCu(OCH3)2, as well as some dialkoxy copper (I) barium derivatives: Ba2Cu4(OC(C2H5)3)8, BaCu6(OC(C2H5)3)8, BaCu2(OC(CH3)3)4 and polymers or oligomers thereof (Purdy “Structure and properties of heterometallic alkoxides containing copper (I)” Polyhedron 1995, 14, 761 and “Crystal structures of the Ba—Cu(I) alkoxides Ba4Cu6(O)(OCEt3)12 and BaCu6(OCEt3)8” Polyhedron 1998, 17, 4041). However, no information is available regarding reactivity of these compounds toward fluoroform.
For the reasons stated above, it is needed to develop a method for obtaining a trifluoromethyl copper composition directly from a copper reagent and fluoroform, which is useful for synthetic transformations leading to the introduction of the trifluoromethyl group into other molecules in order to make useful materials.